A number of patents and publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.
Throughout this specification, including the claims which follow, unless the context requires otherwise, the word “comprise,” and variations such as “comprises” and “comprising,” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a pharmaceutical carrier” includes mixtures of two or more such carriers, and the like.
Ranges are often expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood that the particular value forms another embodiment.
This disclosure includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Conditions of dementia such as Alzheimer's disease (AD) are frequently characterised by a progressive accumulation of intracellular and/or extracellular deposits of proteinaceous structures such as β-amyloid plaques and neurofibrillary tangles (NFTs) in the brains of affected patients. The appearance of these lesions largely correlates with pathological neurofibrillary degeneration and brain atrophy, as well as with cognitive impairment (see, e.g., Mukaetova-Ladinska, E. B., et al., 2000).
In AD, both neuritic plaques and NFTs contain paired helical filaments (PHFs), of which a major constituent is the microtubule-associated protein tau (see, e.g., Wischik et al., 1988). Plaques also contain extracellular β-amyloid fibrils derived from the abnormal processing of amyloid precursor protein (APP) (see, e.g., Kang et al., 1987). An article by Wischik et al. (in ‘Neurobiology of Alzheimer's Disease’) discusses in detail the putative role of tau protein in the pathogenesis of neurodegenerative dementias. Loss of the normal form of tau, accumulation of pathological PHFs, and loss of synapses in the mid-frontal cortex all correlate with associated cognitive impairment. Furthermore, loss of synapses and loss of pyramidal cells both correlate with morphometric measures of tau-reactive neurofibrillary pathology, which parallels, at a molecular level, an almost total redistribution of the tau protein pool from a soluble to a polymerised form (i.e., PHFs) in Alzheimer's disease.
Tau exists in alternatively-spliced isoforms, which contain three or four copies of a repeat sequence corresponding to the microtubule-binding domain (see, e.g., Goedert, M., et al., 1989; and Goedert, M., et al., 1989). Tau in PHFs is proteolytically processed to a core domain (see, e.g., Wischik, C. M., et al., 1988; Wischik et al., 1988; Novak, M., et al., 1993) which is composed of a phase-shifted version of the repeat domain; only three repeats are involved in the stable tau-tau interaction (see, e.g., Jakes, R., et al., 1991). Once formed, PHF-like tau aggregates act as seeds for the further capture and provide a template for proteolytic processing of full-length tau protein (see, e.g., Wischik et al., 1996).
The phase shift which is observed in the repeat domain of tau incorporated into PHFs suggests that the repeat domain undergoes an induced conformational change during incorporation into the filament. During the onset of AD, it is envisaged that this conformational change could be initiated by the binding of tau to a pathological substrate, such as damaged or mutated membrane proteins (see, e.g., Wischik, C. M., et al., 1997, in “Microtubule-associated proteins: modifications in disease”).
In the course of their formation and accumulation, PHFs first assemble to form amorphous aggregates within the cytoplasm, probably from early tau oligomers which become truncated prior to, or in the course of, PHF assembly (see, e.g., Mena, R., et al., 1995; Mena, R., et al., 1996). These filaments then go on to form classical intracellular NFTs. In this state, the PHFs consist of a core of truncated tau and a fuzzy outer coat containing full-length tau (see, e.g., Wischik et al., 1996). The assembly process is exponential, consuming the cellular pool of normal functional tau and inducing new tau synthesis to make up the deficit (see, e.g., Lai, R. Y. K., et al., 1995). Eventually, functional impairment of the neurone progresses to the point of cell death, leaving behind an extracellular NFT. Cell death is highly correlated with the number of extracellular NFTs (see, e.g., Wischik et al., in ‘Neurobiology of Alzheimer's Disease’). As tangles are extruded into the extracellular space, there is progressive loss of the fuzzy outer coat of the neurone with corresponding loss of N-terminal tau immunoreactivity, but preservation of tau immunoreactivity associated with the PHF core (see, e.g., Bondareff, W. et al., 1994).
Measurements of tau and β-amyloid peptides, in lumbar-puncture CSF samples, have been combined to add value in the diagnosis of AD (see, for example, Galasko et al. (1998); Hulstaert et al. (1999); Andreasen et al. (2001)) and to discriminate between AD and controls, and between AD and other degenerative dementias (Hampel et al. (2004)). The validation of such tests, however, with neuropathologically confirmed cases and cases at different stages of development has been limited thus far (Clark et al. (2003); Grossmann, et al. (2005); Engelborghs et al. (2008)). Although such tests and others (Wischik et al. (2001); Carretero et al. (1995)) may provide supportive data towards a diagnosis, lumbar-puncture is more invasive than nuclear medicine-based approaches, and carries a higher risk (see, for example, Villareal, D. T. et al. (1998); Marin, D. B. et al. (1998); and Kuller, L. H. et al., (1998)). EEG-neurological diagnosis has also been developed (see, for example, Vargha-Khadem, F. et al. (1997); Willingham, D. B. (1997); Lakmache, Y. et al. (1995); and Hodges, J. R. et al. (1999)), but in this regard there remains a need for cheap instrumentation which can be used at the point of clinician contact.
In developing a treatment aimed specifically at preventing neurofibrillary degeneration of the Alzheimer-type, there is a critical need to develop, in parallel, non-invasive means of selecting patients for treatment, and monitoring their response to the treatment, according to a defined and reproducible definition of disease progression.
WO 02/075318 discloses ligands for aggregated paired helical filament (PHF). The ligands may be used to label aggregated tau, and particularly extracellular aggregated tau present in neurofibrillary tangles.
Structures presented include those of the sulphonated-benzothiazole compounds shown below:

CH 542 266 discloses benzothiazole compounds for use in the textile industries. A compound disclosed is the benzothiazole structure shown below (identified as compound 73):

WO 01/10854 discloses benzothiazole compounds for use as optical brighteners. A compound disclosed is the benzothiazole structure shown below (identified as compound 10):

WO 2006/014382 discloses benzothiazole compounds for use in methods for imaging areas of amyloid deposition in patients exhibiting dementia in pre-diagnosed states. A compound disclosed is the benzothiazole structure shown below (identified as compound 43):
 Code No. StructureP-001
Lee et al. Bioorg. Med. Chem. Lett. 2008, 18, 1534 discloses benzothiazole compounds for use in detecting β-amyloid fibrils. A number of compounds are disclosed as intermediates for the benzothiazole imaging agents, and two example intermediates are shown below:
Code No.StructureP-002 P-003
WO 2007/020400 discloses benzothiazole compounds for use as in vivo imaging agents for amyloid. A compound disclosed is the benzothiazole structure shown below (identified as compound 8):

Also described are intermediates for the preparation of the benzothiazole imaging agents. The intermediates have the general formula shown below (identified as compounds of formula (IIa)):
                wherein        —R1 is selected from C1-6alkyl, C2-6alkenyl, and C2-6alkynyl;        —R2 is selected from hydrogen, C1-10alkyl, C1-10haloalkyl, C6-14aryl, C6-14arylalkyl, —(CH2CH2O)q—CH3 wherein q is an integer of from 1 to 10;        —R3 is a leaving group; and        —R7, —R8, —R9, and —R10 are selected from a list of substituents.        
Notwithstanding these disclosures, it will be appreciated that the provision of one or more compounds, not previously specifically identified as being effective labels for PHF, would provide a contribution to the art.